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When I first arrived in Liège, the scientific activities of our laboratory focused on the
identification of candidate-genes whose different alleles interfere with the
resistance/susceptibility of animals against infectious diseases. Two genes were being
intensively studied (Mx and OAS) due to their theoretical potential in interfering with the
replicative cycle of several viruses responsible for bovine’s viral pneumonias (Baise et al.,
2004 ; Gerardin et al., 2004 ; Leroy et al., 2005 ; 2006). My work consisted then, in the
identification of other genes potentially implicated in the resistance against the
Paramyxoviruses. The Paramyxoviridae family includes some of the great and ubiquitous
disease-causing viruses of animals, including the bovine parainfluenza type 3, the bovine
respiratory syncytial virus, the Newcastle disease virus, the distemper virus, etc. Evidence
was accumulating that genetic factors were involved both in the control of infectious diseases
(Abel et al., 1991 ; 1995 ; Alcais et al., 1997 ; Jin et al., 1999 ; Martinson et al. 1997 ; Shaw
et al., 1995) and in the regulation of infection levels and clinical presentation (Garcia et al.,
1999 ; Plancoulaine et al., 2000 ; 2003). Thus, identifying genes that control the organism
response to paramyxoviruses was a crucial step in elucidating how they might affect the
pathophysiological processes underlying the severity of the disease induced. Other
experiences done in this laboratory showed us how risky and difficult was any extrapolation of
the mouse results to another species if these results were brought through infection with a
heterologous virus, so we decided to implement this strategy with Sendai virus (SeV), the
archetype organism of the Paramyxoviridae family, from which most of the basic biochemical,
molecular and biologic properties of the whole family were derived from (Chanock et al.,
2001). With this goal in mind my thesis was divided in five successive steps: In order to
establish a standard model of SeV infection, the first step consisted in determining the best
volume of inoculum that was needed to achieve a safe, reproducible pulmonary deposition of
Sendai virus in the mice lungs. Secondly we developed a murine model of SeV infection using
a series of different and sophisticated procedures that allowed a quantitative assessment of
disease severity and progression. Then we compared SeV infections among 6 strains of mice
that were deliberately chosen because they originated from different lineages, as deduced
from known genealogical and phylogenetic data. Applying these procedures to distinct inbred
strains of mice, revealed highly significant differences in susceptibility between them. More
specifically 129/Sv were highly susceptible while BALB/c were particularly resistant, BALB/c
exhibiting a benign and asymptomatic affection of the epithelium of the airways, with no
functional impact, generating slight mononucleated cell infiltration, in which viral replication is
repressed and the virus swiftly eliminated. As a result, in the fourth part of my study we
discussed a series of hypotheses that should be tested in the future to improve our
understanding of why BALB/c is so resistant to SeV infection. Practically speaking, our studies
led to the gathering of a genomic DNA collection from the parental extreme lines in terms of
susceptibility (129/Sv) and resistance (BALB/c) and their F1 and F2 offspring. Within this
bank, each of the 263 DNA sample is associated with a portfolio of phenotypic values that are
estimators of the resistance each mouse opposed to the SeV. We hope that, between expert
hands, this bank will allow the detection of genes of which the alleles contribute, at least in
part, to the spectacular resistance of BALB/c. The last part of my thesis consisted in applying
our model to establish if the receptor TLR4 influenced the pathophysiology of the
Paramyxoviridae in general. Because the role of this receptor had already been excluded for
SeV, we tested another virus of the same family and homologous for the mice, the PVM
(standing for pneumonia virus of mice). This work showed, in contradiction of what had been
found in heterologous models in the past, that TLR4 is not involved in host defense against
respiratory tract infection with the Paramyxoviridae.